Patients randomized to 12 weeks of trastuzumab (Herceptin) and lapatinib (Tykerb), in addition to endocrine therapy, had a pCR rate of 12% compared with 28% for patients who received 24 weeks of therapy. Hormone receptor-negative tumors responded better at 12 weeks, whereas HR-positive tumors benefited more from dual anti-HER2 therapy at 24 weeks.

In designing the trial, investigators assumed that 24 weeks of therapy would increase the pCR rate from 27% with 12 weeks of treatment (as reported in a previous trial) to 45%, reported Mothaffar F. Rimawi, MD, of Baylor College of Medicine in Houston, at the San Antonio Breast Cancer Symposium.

The trial's failure to meet the primary endpoint "was mainly due to lower than expected pCR in both arms," Rimawi said. "However, our study demonstrated a twofold numeric increase in pCR in the 24-week arm over the 12-week arm. That increase was more than threefold in the HR-positive subgroup."

"This is the first trial to show that longer treatment with dual anti-HER2 therapy in combination with endocrine therapy, and without chemotherapy, leads to a meaningful increase in pCR rate in HR-positive, HER2-positive breast cancer," he added.

In a previous study, Rimawi and colleagues found that 12 weeks of neoadjuvant therapy with trastuzumab and lapatinib resulted in a pCR rate of 27% and low-volume residual disease in 22%. Whether a longer duration of therapy would improve the pCR rate remained unclear, providing a rationale for a randomized trial of 12 versus 24 weeks of dual anti-HER2 treatment before surgery.

Investigators hypothesized that longer-duration neoadjuvant therapy would improve the pCR rate. They further hypothesized that the addition of endocrine therapy would result in a higher pCR rate in patients with HR-positive tumors.

Rimawi and colleagues enrolled patients with stage II-III HER2-positive breast cancer and randomized them 1:2 to 12 or 24 weeks of neoadjuvant therapy. Patients with HR-positive breast cancer also received endocrine therapy. Biopsies were performed at baseline and week 12 in all patients and at week 24 in patients randomized to the longer-duration anti-HER2 therapy.

The trial had a primary endpoint of pCR in the breast (ypT0-is ypNx). Secondary endpoints included safety and tolerability, time to first recurrence, and overall survival.

The investigators estimated that 86 to 96 patients would be required to detect an increase in pCR from 27% (reported in the earlier study) to 45%, with a power of 85% and type 1 error of 10%. The two treatment arms lacked statistical power for direct comparisons with each other, Rimawi said.

Investigators enrolled 94 patients for the primary analysis. The patients had a median age of 51, and 55 (59%) were older than 50. Postmenopausal women accounted for 52 (55%) of the patients, and whites accounted for three-fourths of the total population.

Grade 3 toxicity occurred more often with the 24-week regimen but was uncommon in both groups. In the 24-week arm, grade 3 liver function tests occurred in five patients and grade 3 diarrhea and mucositis in one patient each. In the 12-week arm, one patient each had grade 3 anemia and renal calculi. No grade 4 toxicity occurred in either group.

Although extended-duration therapy doubled the pCR rate, the 24-week regimen did not meet the prespecified pCR goal of 45%. Analysis of the data by HR status showed that 24 weeks of treatment resulted in a pCR rate of 33% in HR-positive patients versus 9% for the 12-week regimen. The proportion of patients who had ≤1 cm of residual tumor was 35% in the 12-week group and 13% in the 24-week group.

In the HR-negative subgroup, 12-weeks of dual anti-HER2 therapy resulted in a pCR rate of 20% and no patients with ≤1 cm residual tumor. In the 24-week group, the pCR rate was 18% and an additional 18% of the patients had residual disease ≤1 cm.

Rimawi disclosed a relevant relationship with GlaxoSmithKline.

One or more co-authors disclosed relevant relationships with AstraZeneca, Novartis, Pfizer, Genentech, and Nostring.

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